Human Usher syndrome, the most frequent cause of deaf blindness, affects about 1 in 17,000 Americans and is characterized by retinal degeneration due to progressive loss of photoreceptors and congenital deafness. Although at least 12 different loci have been linked to Usher syndrome and we know the identity of nine genes, etiology of the disease and underlying mechanisms are still poorly understood. Based on studies of animal models of Usher syndrome, we propose a new explanation for vision loss; damage to outer segments and subsequent death of photoreceptors is due to an earlier primary defect during photoreceptor development. We hypothesize that Ush2a and Ush2c act in a complex with other Usher proteins, all bound to Ushlc, to mediate reciprocal signaling between photoreceptors and second order neurons. This signaling is required for proper synapse formation and maintenance. Defects in Usher mediated signaling lead to synaptic dysfunction and apoptosis. To test this hypothesis we will 1) learn whether Ush2a and Ush2c signaling mediates synapse formation and maintenance and 2) where and how Ush2a and Ush2c interact with other Usher proteins. These experiments will help reveal the cellular and biochemical mechanisms that underlie Usher syndrome, allow us to assemble the Usher genes into a genetic network and elucidate Usher protein interactions. We will also use genetic screens to identify new genes in the Usher network and new mutations in known Usher genes. Together, these analyses will identify the critical components of the Usher gene network and provide an integrated understanding of Usher syndrome.